Ross Baker

Purpose
Pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), has shown efficacy and safety in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received prior covalent BTKi. We report results, to our knowledge, from the first randomized head-to-head comparison of pirtobrutinib versus ibrutinib in BTKi-naïve CLL/SLL in both treatment-naïve (TN) patients and patients with relapsed/refractory (R/R) disease.

Patients and methods
Patients (N = 662) were randomly assigned 1:1 to receive pirtobrutinib or ibrutinib. All patients were BTKi-naïve. Primary end points were overall response rate (ORR) by independent review committee (IRC) among all randomly assigned patients (intention to treat [ITT]) and in patients with R/R disease.

Results
The study met its primary end points, demonstrating statistically significant noninferiority (NI) of IRC-ORR for pirtobrutinib versus ibrutinib in both the ITT (87.0% [95% CI, 82.9 to 90.4] v 78.5% [95% CI, 73.7 to 82.9]; ORR ratio = 1.11 [95% CI, 1.03 to 1.19]; two-sided P < .0001) and R/R populations (n = 437; 84.0% [95% CI, 78.5 to 88.6] v 74.8% [95% CI, 68.5 to 80.4]; ORR ratio = 1.12 [95% CI, 1.02 to 1.24]; two-sided P < .0001). In TN patients (n = 225), IRC-ORR was 92.9% (95% CI, 86.4 to 96.9) with pirtobrutinib versus 85.8% (95% CI, 78.0 to 91.7) with ibrutinib. Investigator assessed ORR results were consistent. Investigator-assessed progression-free survival (PFS) favored pirtobrutinib in the ITT (hazard ratio [HR], 0.57 [95% CI, 0.39 to 0.83]), R/R (HR, 0.73 [95% CI, 0.47 to 1.13]), and TN (HR, 0.24 [95% CI, 0.10 to 0.59]) populations. Cardiac adverse event rates of atrial fibrillation/flutter and hypertension were lower with pirtobrutinib.

Conclusion
Pirtobrutinib demonstrated NI of ORR versus ibrutinib, with a favorable early PFS trend, particularly in TN patients, and a favorable safety profile including low rates of atrial fibrillation and hypertension.

Trial registration: ClinicalTrials.gov NCT05254743.

Introduction. Patients with high-risk smoldering multiple myeloma (SMM) may benefit from early treatment. With SMM risk stratification advancement, post hoc analysis of the AQUILA study using IMWG 2020 (“20/2/20”) and other risk models was conducted to assess which patients benefited most from daratumumab. Safety and efficacy analyses by age and stem cell collection outcomes were also assessed.

Methods. Patients with confirmed high-risk SMM per IMWG 2014 criteria were randomized to receive subcutaneous daratumumab or active monitoring for 39 cycles, 36 months, or until confirmed disease progression, whichever came first. The primary endpoint was progression-free survival (PFS); secondary endpoints included time to 1L treatment and overall survival. Outcomes were assessed by age, IMWG 2020 high-risk SMM criteria, and IMWG 2020 plus cytogenetic criteria.

Results. Daratumumab showed PFS benefit across all IMWG 2020 subgroups (low-risk: HR=0.59; intermediate-risk: HR=0.70), with largest benefit in the high-risk subgroup; disease progression/death rate with active monitoring was 1.6-fold greater than daratumumab (62.8% vs 37.5%; HR=0.36). Daratumumab benefit was durable, with 5-year PFS rates of 78.2% vs 71.6%, 56.2% vs 42.9%, and 60.4% vs 23.6% in IMWG 2020 low-, intermediate-, and high-risk groups, respectively. A favorable trend for daratumumab in time to 1L treatment was seen across all IMWG 2020 risk groups (low-risk HR=0.63; 95% CI, 0.22–1.80; intermediate-risk HR=0.57; 95% CI, 0.35–0.92; high-risk HR=0.39; 95% CI, 0.25–0.62). PFS benefit occurred regardless of age, in younger (<65y HR, 0.51; 95% CI, 0.32–0.79) vs older (≥65y, HR=0.50; 95% CI, 0.32–0.77) patients. Treatment-emergent adverse event (TEAE) incidence was consistent across the <65, 65 to <75, and ≥75 year subgroups (82.7%, 81.1%, and 87.5% with active monitoring; 96.2%, 98.5%, and 95.2% with daratumumab). Serious TEAEs were more frequently observed in older active monitoring patients (12.2%, 18.9%, and 50.0% with active monitoring; 24.8%, 35.8%, and 28.6% with daratumumab). In daratumumab and active monitoring arms, respectively, 23 (11.9%) and 41 (20.9%) patients received autologous stem cell transplant after active MM progression, with limited plerixafor use (daratumumab, 3 [1.6%] vs active monitoring, 9 [4.6%]). The median (range) CD34+ cell yield was 5.0 (2–20)×106 cells/kg body weight among 22 patients in the daratumumab arm and 5.1 (2–21)×106 cells/kg body weight among 39 patients in the active monitoring arm.

Conclusions. Patients receiving daratumumab experienced long-term PFS benefits across IMWG 2020 subgroups, with the largest benefit seen in high-risk patients. No notable differences in PFS or safety were observed across age subgroups. Early daratumumab treatment for high-risk SMM did not have a detrimental impact on stem cell yield. These results support early intervention with daratumumab monotherapy among patients with high-risk SMM.

Background
Von Willebrand disease (VWD) has 6 categories of either quantitative or qualitative abnormality of von Willebrand factor (VWF). As our understanding of the pathophysiology of VWD improves, there is a need to re-evaluate the classification system consistently. The International Society of Thrombosis and Haemostasis (ISTH) VWF Scientific and standardisation committee (SSC) sought endorsement from the ISTH membership to change the VWD classification to include type 1C VWD (increased VWF clearance) and Type 2M-P VWD (platelet binding defect) and Type 2M-C VWD (collagen binding defect).

Method
After approval of the VWF SSC, the proposals and scientific justification for each VWD classification change were presented at the ISTH VWF SSC virtual 2020 Congress. This was followed by an online vote of the ISTH community promoted via the ISTH Congress, the VWF SSC mailing list, and social media. It was open from July 2020 to December 2020, with an a priori criteria of at least 75% approval to endorse the proposed subtypes.

Results
The inclusion of Type 1C VWD was confirmed with an approval of 94.2%. Although type 2M-P VWD and Type 2M-C VWD had merit, they did not meet the required threshold for approval (71.9%).

Conclusion
There was an overwhelming endorsement for including Type 1C in the VWD classification, which occurs in around 20% of Type 1 VWD patients with a shortened VWF survival. Although generally supported, the threshold was not met to include the subcategorization of Type 2M-P VWD and Type 2M-C VWD.

Direct oral anticoagulants (DOACs) are widely prescribed to prevent and treat venous and arterial thromboembolism, supported by published evidence, and are preferred over warfarin in many guidelines. Although the risk of major bleeding, in particular intracranial haemorrhage (ICH), is decreased with DOACs, gastrointestinal bleeding is increased with some DOACs, and the case fatality rate of bleeding remains high. Therefore, it is important to (i) prescribe DOACs appropriately, (ii) have strategies to manage major bleeding including the use of specific reversal agents and (iii) interrupt and resume DOACs for procedures. The main recommendations are as follows: (i) Select the appropriate dose of DOAC according to indications and consider patient factors to minimise bleeding risks; (ii) DOACs do not require routine laboratory testing; (iii) for life‐threatening uncontrollable bleeding, specific agents can be used to reverse the anticoagulant effects of DOACs; and (iv) DOACs can be interrupted for planned procedures without the need for ‘bridging’ with low‐molecular‐weight heparin (LMWH). The anticoagulant effects of DOACs can be reversed with specific agents, such as andexanet for apixaban and rivaroxaban and idarucizumab for dabigatran. If not available, pro‐haemostatic agents such as prothrombin complex concentrates or activated prothrombin complex concentrates can be considered. DOACs can be interrupted and resumed for procedures without the need for ‘bridging’ with LMWH.

The classical Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) is a heterogeneous group of clonal hematopoietic stem cell disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These disorders are characterized by one of the shared driver mutations, JAK2, calreticulin (CALR), and MPL, which result in consecutive activation of the JAK-STAT signaling pathway, eventually leading to abnormal hematopoietic cell proliferation and excessive cytokine production. Although MPNs have traditionally been considered diseases of older adults–given a median age at diagnosis in the 60s–their occurrence in adolescents and young adults is increasingly recognized, with 10-20% of cases diagnosed before the age of 40.3 Among this younger population, ET is the most common subtype and displays a female predominance (65-70%), highlighting the clinical importance of reproductive health and pregnancy considerations. Additionally, the trend toward advanced maternal age further contributes to the growing number of pregnant patients with MPN. Pregnancy in women with MPN poses unique challenges (Figure 1). Thrombosis and bleeding are common complications that contribute to significant morbidity and mortality in MPNs. Consequently, the prevention of thrombotic events is considered one of the primary goals in the management of MPN and therapeutic options are considered based on an individual’s thrombotic and bleeding risk profile. Pregnancy by itself is a pro-thrombotic state, driven by estrogen-mediated changes in coagulation and fibrinolysis. The risk of venous thromboembolism (VTE) is increased approximately 4-to 5-fold during pregnancy, and up to 20-fold in the postpartum period, compared to nonpregnant women. When compounded by MPN, this baseline risk escalates further, presenting considerable challenges to fetal and maternal outcomes. In women of childbearing age presenting with unusual thrombotic events–particularly in atypical sites such as the splanchnic or cerebral veins–a complete blood count (CBC) should be reviewed closely for features suggestive of an underlying MPN, including erythrocytosis, leukocytosis, or thrombocytosis. Importantly, initial clinical presentation leading to a diagnosis of a MPN in women of reproductive age may differ substantially from the classic presentations seen in older populations. In some cases, diagnosis may follow a venous or arterial thrombotic event, while in others it may be triggered by recurrent pregnancy loss, abnormal uterine bleeding, or other atypical bleeding symptoms. In many women, the diagnosis may even arise incidentally through routine blood work. These diverse presentations are not well captured in current studies but are clinically important, as each scenario may require a tailored diagnostic and management approach, particularly in the context of pregnancy or fertility planning...

Introduction
Warfarin (vitamin K antagonist) remains an established anticoagulant for patients at high risk of arterial and venous thromboembolism. The prompt reversal of the anticoagulant effect of warfarin is necessary in the context of major bleeding or emergency surgery because of its extended inhibition of vitamin K-dependent coagulation factors for days. The mainstay of urgent warfarin reversal has been vitamin K administration, and infusion of a three-factor prothrombin complex concentrate (3FPCC) and the option for the addition of fresh frozen plasma as a source of factor VII. With the upcoming introduction in Australia and New Zealand of a four-factor prothrombin complex concentrate (4FPCC), which replaces all the vitamin K-dependent clotting factors, this article updates the previously published warfarin reversal guidelines.

Main recommendations
For urgent warfarin reversal, 4FPCC should be used instead of 3FPCC, using the same suggested dose. Vitamin K co-administration is still recommended for more sustained reversal.

Changes in management as a result of this statement
The use of 4FPCC for urgent warfarin reversal obviates the need for co-administration of fresh frozen plasma.

Myelofibrosis (MF) is a progressive disease characterized by accumulation of extracellular matrix (ECM) in the bone marrow (BM) which impairs normal hematopoiesis. While Janus kinase (JAK) inhibitors reduce spleen volume and provide symptomatic improvement, they do not resolve BM fibrosis and may cause or exacerbate anemia and thrombocytopenia. An anti-fibrotic therapy capable of normalising BM microenvironment and function remains a significant gap in the current treatment landscape. MF is associated with elevated expression of lysyl oxidases; enzymes responsible for maturation of the most abundant ECM proteins, collagen and elastin. PXS-5505 is a novel pan-lysyl oxidase inhibitor designed to exert an anti-fibrotic mode of action by preventing the cross-linking of collagen and elastin. PXS5505-MF-101 is a multi-center phase 1/2a study of PXS-5505 in MF patients which included a dose escalation phase (DEP) and a cohort expansion phase (CEP). Primary objectives were to determine the safety and tolerability of PXS-5505 and to define dosing for future studies. The DEP demonstrated that the highest dose tested, 200 mg BID, was safe and achieved robust systemic reduction of lysyl oxidase activity; this dose was therefore selected for the CEP. Twentyfour patients (median age 72 years) with relapsed or refractory MF were recruited into the CEP and 54% (13/24) completed 24 weeks of treatment. PXS-5505 was well tolerated and reached steady state concentrations by Day 28. Over the 24-week treatment period preliminary indications of clinical efficacy, including a reduction in BM collagen, were evident. Overall, these data support continued investigation of PXS-5505.

Background
Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.

Methods
In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.


Results
Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.

Conclusions
Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.)